Our laboratory has a strong interest in pharmacogenetics. We have been active in studying how germline genetic variants can alter pharmacokinetics, response, and toxicity of various anticancer agents, thereby contributing to interindividual variation in clinical outcomes in therapies with an already narrow therapeutic window. We have established a molecular link between these polymorphisms and their phenotype as it relates to drug treatment. Most of our work has been focused on genetic variations in drug metabolism and transporting candidate genes such as ABCB1 (P-glycoprotein, MDR1), ABCG2 (BCRP), SLCO1B3 (OATP1B3, OATP8), CYP3A4, CYP3A5, CYP1B1, CYP2C19, CYP2D6, UGT1A1, UGT1A9 and several others. Drug transporters mediate the movement of endobiotics and xenobiotics across biological membranes in multiple organs and in most tissues. As such, they are involved in physiology, development of disease, drug pharmacokinetics, and ultimately the clinical response to a myriad of medications. Genetic variants in transporters cause population-specific differences in drug transport and are responsible for considerable interindividual variation in physiology and pharmacotherapy. Thus, we are interested in studying how inherited variants in transporters are associated with disease etiology, disease state, and the pharmacological treatment of diseases. We are also interested in non-candidate gene approaches where large numbers of polymorphisms are explored to establish a relationship with clinical outcome, and experiments are conducted to validate potential causative alleles resulting from exploratory scanning. We have worked with Affymetrix to beta-test the DMET chip that contains 1,256 genetic variations in 170 drug disposition genes, and are currently establishing a clinical trial where patients treated at the NCI will be genotyped with the DMET chip to explore potential links between these genes and various treatments of several cancers. We are currently making progress in validating the results from the initial DMET chip experiments. While many of these studies have been conducted in order to explain some of the genetic influence on pharmacokinetic variability, we also have a strong interest in clarifying genetic markers of pharmacodynamics and therapeutic outcome of several major anticancer agents since this field has been rather poorly studied. We have evaluated genetic polymorphisms in the XRCC1 gene and its association with radiation therapy in prostate cancer and found that XRCC1 genetic variants may affect the outcome in patients who received radiotherapy for localized prostate cancer. ERCC1 polymorphism & platinum-base chemotherapy: Genetic polymorphisms in ERCC1 are thought to contribute to altered sensitivity to platinum-based chemotherapy. Although ERCC1 N118N (500 C&gt;T, rs11615) is the most studied polymorphism, the impact of this polymorphism on platinum-based chemotherapy remains unclear. This is the first study in which the functional impact of ERCC1 N118N on gene expression and platinum sensitivity was explored. The aim of this study is to investigate if the reduced codon usage frequency of AAT, which contains the variant allele of the silent mutation, has functional impact on ERCC1 in a well-controlled biological system. Specifically, the ERCC1 cDNA clone with either the C or T allele was introduced into an ERCC1 deficient cell line, UV20, and assayed for the effect of the two alleles on ERCC1 transcription, translation and platinum sensitivity. Both ERCC1 mRNA and protein expression levels increased upon cisplatin treatment, peaking at 4h post-treatment, however there were no differences between the two alleles (p&gt;0.05). These data suggest that N118N itself is not related to the phenotypic differences in ERCC1 expression or function, but rather this polymorphism may be linked to other causative variants or haplotypes. Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: Implications of genetic variants on sorafenib exposure and sorafenib-induced hyperbilirubinemia. Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation in vitro. The DMET genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C&gt;T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles. UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C&gt;T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib. Romidepsin causes a number of cardiac effects, one of which is heart rate changes. We compared three polymorphisms in the cardiac transporter, ABCB1 (MDR1, P-gp), to heart rate changes following romidepsin treatment in 64 patients. The ABCB1 alleles that were previously associated with increased intracardiac ABCB1 expression were also related to the smallest increases in heart rate following infusion (P=0.033). We conclude that ABCB1 polymorphic variants are related to romidepsin-induced heart rate increases. ABCB1 polymorphisms are associated with variability in exposure to docetaxel and 99mTc-sestamibi before and after tariquidar coadministration. The ABCB1 (P-gp) inhibitor, tariquidar, is not associated with increases in docetaxel pharmacokinetics (PK); however, the impact of variants in ABCB1 have not been studied with this combination. We hypothesized that individuals carrying variants associated with decreased ABCB1 expression and efflux capability would have greater changes in docetaxel PK following tariquidar. Preliminary analyses suggest that individuals carrying ABCB1 variants have similar baseline plasma docetaxel AUC when compared to those carrying wild-type alleles; however, the tissue distribution of an ABCB1 model substrate (99mTc-sestamibi) at baseline appears be greater in extrahepatic tissues of those carrying variant ABCB1 diplotypes. Tariquidar coadministration with docetaxel and sestamibi appears to alter plasma pharmacokinetics and tissue distribution of these compounds differently based on ABCB1 genotype. Wildtype ABCB1 carriers experienced an increase in plasma docetaxel exposure, an increase in the volume of distribution of docetaxel, and an increase in the concentration of sestamibi in heart, lung, and tumors as compared to patients carrying variant alleles. Therefore, it appears that ABCB1 alleles heavily influence the biodistribution of docetaxel and sestamibi into the bodily tissues thereby affecting toxicity and efficacy.